Abstraction:

Several surveies have evaluated the consequence of matrix metalloproteinase 9 ( MMP-9 ) look on the overall endurance in osteogenic sarcoma patients, but the consequences remain conflicting. To analyze the predictive significance of MMP-9 look in osteogenic sarcoma hazard, we conducted this meta-analysis to consistently reexamine the published surveies. We searched the normally used electronic databases updated to September 2013 for relevant surveies which evaluate the rectification between MMP-9 look and endurance of patients with osteogenic sarcoma. Overall, a sum of 8 surveies including 437 instances were screened out. No important heterogeneousness was observed between surveies. The MMP-9 was expressed in 73.9 % ( 323/437 ) of instances, and the consequences showed that MMP-9 look was associated with increased the osteogenic sarcoma hazard during the follow-up ( ( RR=2.79, 95 % CI=1.96-3.97, P & A ; lt ; 0.00001 ) . By ethnicity analysis, a important rectification was besides found between MMP-9 look and osteogenic sarcoma hazard among Asiatic and non-Asian population ( P & A ; lt ; 0.001 ) , bespeaking that MMP-9 is an index of forecast of osteogenic sarcoma. In decisions, this meta-analysis indicated that MMP-9 look might be a biomarker of hapless forecast for patients with osteogenic sarcoma. However, the predictive value of MMP-9 on endurance of osteogenic sarcoma patients still needs farther large-scale tests to be clarified.

Keywords:osteogenic sarcoma, matrix metalloproteinase 9, meta-analysis

1 Introduction

Osteosarcoma is the most frequent bone tumour in kids and striplings ( Ritter and Bielack, 2010 ) . The incidence of osteogenic sarcoma in the general population is 2-3 per million each twelvemonth ( Ottaviani and Jaffe, 2009 ) . Although modern protocols such as chemotherapy, surgery, and sometimes radiation therapy are employed to be as the oncological intervention methods which have improved the overall endurance for osteogenic sarcoma patients, the 5-year endurance rate remains at 60 % –70 % during the last past old ages ( Bielack et al. , 2002 ) . Hence, there is a existent demand to develop fresh attacks for handling osteogenic sarcoma and to research better indexs for patients with hapless forecast at the clip of diagnosing.

Recently, research workers chiefly investigate the possible function of biological factors ( as predictive markers ) which involved in the carcinogenic procedure of osteogenic sarcoma. They have demonstrated that predictive factors are really of import for clinicians to choose the best interventions for patients with osteogenic sarcoma ( Poletajew et al. , 2011 ) . Matrix metalloproteinase ( MMPs ) are a household of enzymes that play of import functions in both physiological and pathological procedures of the bone ( Bjornland et al. , 2005 ) . They have long been proved to be associated with malignant neoplastic disease cell invasion and metastasis, which are involved in tumour growing, tissue invasion, and metastasis ( Kessenbrock et al. , 2010, Morrison et al. , 2009 ) . Matrix metalloproteinase 9 ( MMP-9 ) is a matrix-degrading enzyme that plays a important function in a assortment of stromal reactions, including neovascularization both in normal tissues and tumours ( Kim and Kim, 1999 ) . Tumor cells produced the MMP-9, tie ining with the metastases ( Kido et al. , 1999 ) . Metastatic lesions of osteogenic sarcoma was shown to be strongly associated with MMP-9 in kids ( Himelstein et al. , 1998 ) .

Several retrospective surveies have evaluated whether MMP-9 may be a predictive factor for endurance in patients with osteogenic sarcoma. However, no consensus of consequences has been reached. Therefore, we conducted this meta-analysis of eligible surveies associating MMP-9 with the clinical result in patients of osteogenic sarcoma to find whether MMP-9 look was a potentially utile marker.

2 Materials and methods

2.1Search scheme and eligibility standards

A comprehensive hunt was conducted utilizing the undermentioned electronic databases PubMed, Embase, Medline Wanfang and CNKI ( China National Knowledge Infrastructure ) to retrieval relevant surveies. An upper day of the month bound of September 2013 was applied. The Medical Subject Heading ( MeSH ) footings “osteosarcoma” , “osteogenic sarcoma” , “bone tumor” , “MMP-9” and “matrix metalloproteinase 9” every bit good as their combinations were employed as the searching words. The corresponding Chinese footings were used in the Chinese library. Mentions were besides checked for other relevant publications.

2.2Standards for article showing

Surveies eligible for inclusion in this meta-analysis must run into the undermentioned standards: 1 ) patients with osteogenic sarcomas were confirmed ; 2 ) step the relationship between MMP-9 look and osteosarcoma patient endurance ; 3 ) have a follow-up clip transcending 3 old ages ; 4 ) all the related informations were available to pull out ; and 5 ) if the same writers reported two or more publications on the same issues and population, merely the most recent survey was included.

2.3Data Extraction

Two experts independently assessed the quality of included surveies to make a consensus on all of the points. The undermentioned informations were retrieved from each study: first writer, publication twelvemonth, ethnicity, phase, method and isoforms, definition of positiveness, figure of patients, ?3-year endurance and mortality rate.

2.4Statistical analysis

The hazard ratio ( RR ) with its 95 % assurance intervals ( CI ) was employed to measure the predictive function of MMP-9 look in osteogenic sarcoma. The Z trial was used to find the significance of the pooled RR with a P value less than 0.05 sing important. The heterogeneousness among included articles was evaluated utilizing the Q trial and I2statistics. The fixed-effect theoretical account was used when the P-value more than 0.1 for the Q trial and I2less than 50 % . Otherwise, the random-effect theoretical account was used. The funnel secret plan was performed to analyze the publication prejudice. Analysiss were carried out utilizing the Review director 5.2 ( The Cochrane Collaboration ) . All trials were two sided.

3 Consequences

3.1Study choice and features

The electronic database hunt foremost identified 197 mentions. Following the rubric and abstract screened for relevancy, 18 full-text articles comprehensively assessed against inclusion standards. Overall, a sum of 8 prospective cohort surveies were able to read the full text and eventually included in this reappraisal. Figure 1 showed the survey flow.

The entire figure of patients included in this meta-analysis was 437, runing from 40 to 70 patients per survey. MMP-9 was expressed strongly in 73.9 % of instances. The surveies were conducted in four states and published between 2001 and 2010. Of the six include surveies, five were from China ( Chen et al. , 2001, Li et al. , 2004, Luo and Ni, 2006, Li et al. , 2006, Huang and Huang, 2009 ) , one was from Japan ( Uchibori et al. , 2006 ) , one was from Russia ( Kushlinsky et al. , 2010 ) and one was from England ( Foukas et al. , 2002 ) . All patients in the eligible surveies were determined by pathological phase. The major features of the eight eligible publications were reported in Table 1.

3.2 Meta-analysis

The consequences of MMP-9 look in endurance of osteogenic sarcoma patients were listed in Table 2. The heterogeneousness between surveies was non important and the fixed-effect theoretical account was employed for ciphering the pooled RR ( I2=0 % ) . Overall, our consequences showed that MMP-9 look was associated with increased the osteogenic sarcoma hazard in patients during the follow-up ( RR=2.79, 95 % CI=1.96-3.97, P & A ; lt ; 0.00001 ) , bespeaking that MMP-9 was a predictive index of osteogenic sarcoma as shown in Figure 2. When measuring the consequence of MMP-9 look by ethnicity, we found significantly association in both Asiatic population ( RR=2.61, 95 % CI=1.79-3.81, P & A ; lt ; 0.00001 ) and non-Asian population ( RR=3.86, 95 % CI=1.48-10.07, P=0.006 ) , as shown in Figure 3. No heterogeneousness was found between these two groups ( P=0.73, I2=0 % ) .

3.3Sensitivity analysisand Publication prejudice

The influence of individual survey on the overall consequence was investigated by canceling one survey at a clip, severally, and the consequence showed that the hazard ratio was non significantly changed. The funnel secret plan for this meta-analysis of the predictive function of MMP-9 look in patients with osteogenic sarcoma revealed no grounds of dissymmetry ( Figure 4 ) . Therefore, there was no possibility of publication prejudice hazard in the meta-analysis.

4 Discussion

Osteosarcoma is a common primary malignance of bone. Although aggressive chemotherapy regimens have been emerged, 30-50 % of patients still die of pneumonic metastasis ( Geller and Gorlick, 2010, Jaffe, 2009 ) . There are no important betterments in forecast, presenting and surgical direction of osteogenic sarcoma. As the molecular pathogenesis of osteogenic sarcoma expands, possible curative mark s are being identified ( Hirotsu et al. , 2010, Yang et al. , 2010, PosthumaDeBoer et al. , 2011 ) . Understanding of these mechanisms is of import to better the forecast of patients with osteosarcoma through tumor-targeted therapies.

During the last two decennaries, legion surveies have demonstrated a correlativity between MMPs overexpression and the forecast of assorted sorts of malignant neoplastic disease, including hepatocellular carcinoma, salivary secretory organ malignant neoplastic disease and osteogenic sarcoma ( Ng et al. , 2011, Luukkaa et al. , 2010, Korpi et al. , 2011 ) . For illustration, MMP-2 overexpression was shown to be a hapless forecast for osteogenic sarcoma patients ( Wen et al. , 2013 ) ; vascular endothelial growing factor ( VEGF ) overexpression in osteosarcoma patients indicated a hapless forecast every bit good ( Yu et al. , 2013 ) . A figure of surveies have besides investigated the function of MMP-9 look in osteosarcoma patients but have non yielded a consistent and conclusive consequence. Therefore, to deduce a more precise estimation, the current survey was conducted to consistently look into whether the look of MMP-9 in patients is correlated with the forecast of osteogenic sarcoma.

Overall, our consequences found that MMP-9 look was associated with increased hazard of patients with osteogenic sarcoma ( P & A ; lt ; 0.00001 ) . By ethnicity analysis, we besides found significantly association between MMP-9 look and osteogenic sarcoma hazard among Asiatic population and non-Asian population ( P & A ; lt ; 0.001 ) . Sensitivity analysis suggested that the pooled RR was non changed when canceling each individual survey. Therefore, the meta-analysis suggests that MMP-9 look indicates a poorer forecast for patients with osteogenic sarcoma. Our findings may assist to acquire a precise estimation of the predictive function of MMP-9 look in patients with osteogenic sarcoma.

MMP-9 is a secreted multi-domain enzyme that regulates cell-matrix composing in which the hemopexin, the O-glycosylated and the catalytic spheres yield support for fond regard, articulation and contact action, severally ( Ram et al. , 2006 ) . Biological surveies of MMP-9 have tuned the field from being chiefly cancer-oriented towards vascular and inflammatory research ( Johnson et al. , 2011, Scoditti et al. , 2012 ) . In tumour biological science, it has been progressively appreciated that MMP-9 from inflammatory cells, peculiarly neutrophils, co-determines forecast and result ( Vandooren et al. , 2013 ) . Studies on transplantable osteogenic sarcoma suggest that overexpression of MMP-9 is one of the indispensable factors related to the development of metastatic disease. Restricted MMP-9 activity was associated with fewer metastatic pneumonic lesions, whereas increased activity was associated with a high metastatic potency ( Ma et al. , 2013, Yang et al. , 2013 ) .

MMP-9 is non merely an independent forecast factor for tumours, but besides can tie in with other factors. The look of MMP-9 is association with angiogenic factors such as VEGF has been reported in a assortment of human tumours ( Wang et al. , 2011, Nosaka et al. , 2011 ) . Research workers have demonstrated a close relationship between MMP-2 and MMP-9 look and tumour behaviour, proposing that both they could be involved in the patterned advance of melanocytic precursor lesions to malignant melanoma ( Babykutty et al. , 2012 ) . Pre-ALP correlative with MMP-9 look and lung metastasis ( Han et al. , 2012 ) . On the other manus, the suppression of MMP-9 look contributes to the anti-tumor belongingss. The look of ERK5 regulates the invasion of osteogenic sarcoma cells by bring oning MMP-9 look ( Kim et al. , 2012 ) . Antiviral belongingss of melittin are regulated by keeping MMP-9 look ( Park et al. , 2010 ) .

Several restrictions are presented in our meta-analysis. First, the figure of sample sizes included in this survey was comparatively little. Second, there were no consistent endurance rates among the eligible surveies for the overall endurance rate was used as the primary result. Third, no standard appraisal method was available to measure the precise estimation of the function of MMP-9 look in osteogenic sarcoma. Fourthly, the original information was insufficiently, appraisal of possible interactions was limited.

In decision, our meta-analysis is the first clip to consistently gauge the association between MMP-9 look and endurance of patients with osteogenic sarcoma. The consequences suggest that MMP-9 look is associated with hapless overall endurance in osteogenic sarcoma. However, more surveies with large-scaled specimens and better standardized appraisal of predictive markers are needed to look into the rectification between MMP-9 look and endurance of osteogenic sarcoma.